PROJECT SUMMARY The goal of the Center for Reproductive Science and Medicine at UC San Diego is to develop understanding of the fundamental mechanisms that cause disordered function of the hypothalamic-pituitary-ovarian axis in Polycystic Ovary Syndrome (PCOS). This application represents our renewal for years 34-38. Our productivity has been exceptional with 176 papers published since the submission of our previous award. We continue to produce novel, significant contributions to the reproductive sciences, integrating multidisciplinary clinical, translational, and basic research to facilitate and accelerate the translation of promising new discoveries into clinical medicine. We are proposing three integrated, innovative Research Projects, all with experienced, internationally renowned leaders. The renewal of Project I (Pamela L. Mellon, PL) will address the roles of FSH transcriptional and secretory control in the dysregulation of the neuroendocrine system in mouse models of PCOS and premature ovarian failure. The focus will be on the roles of androgen excess, genetics, epigenetics, and specific single nucleotide polymorphisms in the FSH? gene associated with PCOS. Project II (Mark A. Lawson, PL), a new project, will chart novel territory in understanding the roles of fatty acids and excess androgens in regulating the hypothalamic GnRH pulse generator and GnRH sensitivity at the pituitary in PCOS. Using novel genetically modified mice, highly sensitive assays to measure LH pulses in vivo, mouse models of PCOS, perifusion cell culture models, high-fat diet, and lipid infusions, this Project investigates the roles of free fatty acids and androgens in dysregulation of the hypothalamic-pituitary-ovarian axis and their overall contribution to the PCOS phenotype. The renewal of Project III (R. Jeffrey Chang, PL) will delineate the role of androgens on follicle function implicated in anovulation in clinical studies in women with PCOS and address fundamental mechanisms underlying dysfolliculogenesis in PCOS using a mouse model overexpressing Cyp17. All three projects include teams of very experienced investigators and integrate basic and translational studies to address major aspects of the mechanisms of PCOS. The Projects are highly interactive and synergistic, creating a coherent, mechanistic, and translational research program. The 11 faculty involved in the Center are all at the La Jolla campus of UCSD, most have worked together for many years, and several are new young investigators that have been recruited to or mentored within the Center. The Administrative Core supports the Center, provides the Enrichment Programs, and facilitates interactions within the Center and the NCTRI Program. The new Education/Outreach Core is novel and exciting. Unique strengths of the Center include its translational accomplishments, outstanding faculty, long-term leadership, integration of clinical and basic research, cohesive collaboration, and location at UC San Diego in La Jolla.